Interphotoreceptor retinoid binding protein (IRBP) was studied in retinae of mice with allelic combinations at the rd and rds loci. Until postnatal day 7 (P7), IRBP is located intracellularly in all retinae. Thereafter, in the normal retina, IRBP increases and is found primarily in the interphotoreceptor matrix. In the rd/rd, +/+, and rd/rd, rds/rds mutants, IRBP drops rapidly after P11 and is not secreted but is present intracellularly during the retaining degenerative process. In the rd/rd, rds/rds mutant, IRBP loss significantly precedes visual cell loss. In contrast, retinae of rodless +/+, rds/rds and +/+, rds/+ mutants synthesize essentially normal amounts of IRBP until very late in the degenerative process when there is then a significant amount of intracellular IRBP. We conclude that abnormality in secretion combined with other factors could lead to the degenerated phenotype in mice bearing the rd gene. Four synthetic peptides based on amino acid sequences present in cyanogen bromide peptides of IRBP were shown to induce autoimmune uveitis (EAU) and pinealitis (EAP) in Lewis rats. One of these peptides, containing 23 amino acids, was highly immunopathogenic and also immunodominant. The other peptides were substantially less immunopathogenic and also non-dominant. IRBP was found to provide efficient delivery of retinol to the pigment epithelium for esterification and storage in the eyecup of dark adapted toads (B. Marinus). Purified bovine IRBP was found to be capable of binding exogenous radiolabeled docosahexaenoic acid and palmitic acid.